QP Current Practices Challenges and Mysteries_Almac_March2012

Agenda• QP Roles and Responsibilities• QP Current Practices– Supply Chain Verification– Study Specific Information– Lot Specific Information– QP Release• Mysteries– What happens when things go wrong?

QP Roles andResponsibilities• Qualified Person must:– Ensure product has been manufactured inaccordance with»GMP»Product Specification File»Clinical Trial Application– Certify in a register or equivalentdocument that product satisfies provisionsof Article 13, 2001/20/EC.

QP Roles andResponsibilities• IMPs manufactured in a third country tostandards at least equivalent to EUGMP• How does the QP ensure theserequirements are met in practice?

QP RELEASE PROCESS1. SupplyChainVerification2. StudySpecificInformation3. LotSpecificInformation

QP RELEASE PROCESS1. SupplyChainVerification

Sites to be verified• Chemical Drug Substance– Confirmation of compliance with at leastLocal or National GMP for• Manufacturing• Analytical Testing• Storage– No requirement for QP assessment to EUGMP compliance

Sites to be verified• Biological Drug Substance– QP assessment for compliance with EU orequivalent EU GMP• Working Cell Bank (preparation,maintenance and storage)• Manufacturing• Analytical Testing (release and stability)• Storage

Sites to be verified• Why– Essentially the same as the DP– Difficult to be an Established Process– Greater variation– Higher risk– Member States requirements vary

Sites to be verified• Drug product– QP assessment for compliance with EU orequivalent EU GMP• Manufacturing• Analytical Testing (release and stability)• Storage

Sites to be verifiedWhat does the process involve?• Risk Assessments to formally document theprocess of verification• Identify each site involved• Determine if on-site audit is required• Justification provided if on-site audit is notrequired

Continued…• Who can confirm EU GMP / equivalent EUGMP compliance– European Medicines Agency– EEA member state Competent Authoritye.g MHRA– Competent Authority within a country witha Mutual Recognition Agreement in place– QP– Under the supervision of a QP

Criteria• Scope of the audit appropriate• Outcome satisfactory• Certificate confirming EU/equivalent EU GMPcompliance• Documentation remains valid• Copy of– audit report, audit summary or supportingdocumentation– QP resume or evidence of QP eligibility

QP Declaration• May be confused with the lot specific QPStatement of Release• Signed by QP, confirming…manufacturingsites to be used outside of the EEA operateto equivalent EU GMP standards• Protocol and Product specific• Submitted as part of the CTA to the relevantCompetent Authority• QP is taking personal responsibility forcertifying the sites

QP Declaration• All sites verified- only sites of manufacture,packaging and labelling detailed– Czech Republic- QP Declaration to alsoincluded sites of release and stabilitytesting– Sweden- Details of site verification to beprovided in an additional memo• May be issued at client risk pendingfavourable outcome of inspection/audit• Determined as part of Risk Assessment

Common Pitfalls• All sites used in the supply chain (e.g.analytical testing labs) not identified toQP– Can occur at various stages in the study– Sub contracted sites forgotten– Assessment not performed– Possible delays

Common Pitfalls• Scope of GMP certification does notcover scope of work performed(e.g. manufacturing line or dosage form)– Inspection report covers Buildings 1,2 and3; product manufactured in Building 4– Inspection report covers solid dose- sterileinjectable in the study

Common Pitfalls• Site address or location incorrect (e.g.postal address vs building address)– Inspection report details postal address– Building Address different– Sites of actual manufacture at a separatelocation– Queries could be raised

QP RELEASE PROCESS2. StudySpecificInformation

Study SpecificDocumentation• Remember QP Legal Duties– Each batch of product has beenmanufactured…..according to GMP,Product Specification File (PSF) andClinical Trial Application (CTA)• QP must have knowledge of– CTA which should be consistent with PSF

Continued…• Study Specific Documentation– Clinical Trial Application Form (Annex 1)– Protocol– IMPD / sIMPD / SmPC / CommercialSpecifications– IMPD Summary of Changes Document (ifapplicable)– Master English Label Text and CountrySpecific Text (as submitted)– Almac CTA Questionnaire

Continued…• Document of greatest relevance to the QP….IMPD– Contains the quality data that has beensubmitted to the Competent Authorities• Data provided on– Drug Substance– Drug Products• IMP, Comparator, NIMPs, e.g. Rescuemedication– Placebo

Continued…What is the Product Specification File?• Responsibility of the Sponsor• A ‘changing’ reference document• May consist of a number of ‘files’ in differentlocations• QP MUST have access to any information ifrequired• Assessed by Inspectors

Continued…Contains or makes reference to:– Specifications / Analytical Methods• Starting materials, packaging, intermediate, bulkand finished– Manufacturing Methods– In-process testing & methods– Approved Label Text– Randomisation Codes– Technical Agreements– Stability Data– Storage & Shipment information

Common Pitfalls• Changes to the IMPD need to becommunicated immediately• Why?– Newly imported lots (including new importsfrom bulk lots previously released) need tocomply with the currently approved versionof the CTA i.e. IMPD in the intendedcountry for release– May result in delay of release

QP RELEASE PROCESS3. LotSpecificInformation

Lot Specific Information• Remember QP Legal Duties….– Each batch of product has beenmanufactured and assembled according toGMP, PSF and Clinical Trial Application• QP must therefore have knowledge of thespecific lot of– Drug Substance– Drug Product– Placebo

Documentation requiredFor Drug Substance, Drug Product, Placebo• Certificate of Analysis– To verify compliance with the specification inthe IMPD / sIMPD• Lot specific GMP Statement for the manufacture,testing & packaging / labelling– To verify manufacture in accordance withGMP

Continued…• Critical or major deviations / Out of Specificationinvestigations for manufacture / storage / testing– Drug Product– Placebo• Why?– To identify any possible impact on• Product quality• Patient Safety

Continued…• Biological Drug Substance– Critical or major deviations / OOS for APImanufacture /storage / testing• Why?– GMP starts from maintenance of the WorkingCell Bank– QP must assess to identify possible impact on• Product quality• Patient safety

Continued…• Stability Memo and supporting stability data– In support of extension plan– Must be comprehensive– Substantial Amendment may need to be filed later• Why?– QP must confirm shelf life for Drug Productcomplies with available stability data.

Continued…• Memo to confirm the Manufacturing and testingsites as applicable• Why?– To confirm supply chain remains inaccordance with• IMPD/sIMPD• QP Declaration (if applicable)

Continued• Documentation required for EU Licensed DrugProducts– Commercial pack direct from manufacturer• QP Certification– Wholesale dealer• Statement of Authenticity / ‘Pedigreedocument’– Manufacturer supplied Brite Stock• Memo from QP to confirm productcompliance with MA with any exceptionsidentified (e.g. labelling)

Continued• Non- EU Licensed Drug Products– Difficulties when establishing supply chain– Confirm EU GMP / EU GMP equivalency ofsupply chain– Preference is to use EU licensed DrugProducts where possible– The specific documents required areassessed on a case by case basis• QP involved during submission• Advise on exact means of verification– Recent Almac experience- MHRA acceptance

Common Pitfalls• Finished Goods Lot– Is the entire supply chain for product to bereleased consistent with IMPD / QPDeclaration?– Are the languages on the labels consistent withthe destination countries?– Cold chain product – Any temperatureexcursions justified?

ContinuedLicensed Drug Products– Does the CTA take into account anymodification in relation to the MA or equivalent?– Are NIMPs in the study truly NIMPs?– Is the Drug Product the same as that detailed inthe CTA?– Is the expiry date the same or less than theexpiry date of the licensed lot?– Be wary of counterfeit material?

Common pitfalls- Shelf life detailed in IMPD not reflected indrug product labelling- Regulatory Authorities or QP not informed ofchanges- Critical path- may result in delay in QPRelease!

QP release• Remember QP Legal Duties…QP is to certifybatches prior to use in a Clinical Trial– Study Specific and Lot specific informationin place– QP release• Lots specific Checklist– Details checks to verify compliance• CTA Questionnaire– Provides details of regulatory status incountry for release– Blinded QP Statement of Release

Updates• Annex 13 compliant– Manufacturer’s Authorisation Number– Expiry date• IVR controlled– Strongly controlled within inventory whenlabel does not detail expiry date– Challenges to sponsor when product leavesQP inventory system– Is there adequate control at patient level?– Enhanced regulatory scrutiny in QP’sinvolvement in IVRS design

Updates• QP Facilitation Programme at site– Aimed to remove QP release from thecritical path– Quality Compliance Manager placed onsite– Information gathering– Establishing relationships– Educating– Beneficial to both Sponsor and Almac

Mysteries• What happens when things go wrong?– Controls in place have not been ‘effective’?• Manufacturing sites – inspectionsindicate critical findings• Lot specific non conformities identifiedpost release• Recall– Panic- not an option

Continued…• Common goal for both Sponsor and QP– Patient Safety– Maintain Drug Supply– Minimal study impact• Communication of paramount importance– Sponsor and QP– QP and Regulators

Continued• Additional information required• Sponsor supplied Risk Assessment• Almac Risk Assessment– Impact Assessment• Discussions with Regulator as required• Outcome determined; Product to– Remain at site– Be recalled– Be released

Summary• QP Roles and Responsibilities• QP Current Practices– Supply Chain Verification– Study Specific Information– Lot Specific Information– QP Release• Mysteries– What happens when things go wrong?